1. Field of the Invention
The present invention relates to methods for the treatment or prevention of disease states induced by activation of the A2B receptor and mast cell activation.
2. Description of the Related Art
A key early event in allergic responses is the activation of mast cells by allergens. For example, in asthma, exposure to an allergen such as ragweed, triggers the release of allergic mediators such as histamine, leukotrienes, etc. from mast cells. The action of allergens to trigger mast cell degranulation is enhanced by adenosine in asthmatics, but not in non-asthmatics (Bjorck T, Gustafsson L E, Dahlen S E: Isolated bronchi from asthmatics are hyper responsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am.Rev.Respir.Dis. 1992;145:1087-1091). Theophylline is a xanthine that is known to block adenosine receptors and is effective therapeutically to treat asthma (Barnes P J, Pauwels R A: Theophylline in the management of asthma: time for reappraisal?. European.Respiratory.Journal. 1994;7:579-591). For this reason, theophylline is thought to ameliorate the symptoms of asthma, at least in part by blocking adenosine receptors. However, enprofylline, another xanthine that also is used to treat asthma in Europe, was found not to block adenosine receptors in the therapeutic concentration range of 20-50 uM (Chapman K R, Ljungholn K, Kallen A: Long-term xanthine therapy of asthma. Enprofylline and theophylline compared. International Enprofylline Study Group. Chest 1994; 106:1407-1413). Hence it was concluded that enprofylline does not work by blocking adenosine receptors. However, this conclusion was based on an examination of enprofylline binding only to two of the four known adenosine receptor subtypes, A1 and A2A receptors.
Applicant and others have recently discovered that the A3 adenosine receptor on mast cells are responsible for adenosine-stimulated release of allergic mediators in rodent species (Jin X, Shepherd R K, Duling B R, Linden J: Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J.Clin.Invest. 1997;100:2849-2857; Ramkumar V, Stiles G L, Beaven M A, Ali H: The A.sub.3 adenosine receptor is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. J.Biol.Chem. 1993;268:16887-16890). These findings are misleading in that applicant has found that the A3 receptor is not involved in the release of allergic mediators from other species, including human and dog. Rather, applicant discovered that in canine and human mast cells the A2B and not the A3 adenosine receptor is responsible for adenosine-facilitated mast cell degranulation (Auchampach J A, Jin J, Wan T C, Caughey G H, Linden J: Canine mast cell adenosine receptors: cloning and expression of the A3 receptors and evidence that degranulation is mediated by the A2B receptor. Mol.Pharmacol. 1997;52:846-860). FIG. 1 of the instant application shows that NECA (a nonselective agonist that activates A2B and A3 receptors) causes intracellular Ca.sup.2+ and cyclic AMP accumulation in the human mast cell line, HMC-1. IB-MECA, a potent and selective agonist of the A3 receptor is poorly effective. These data suggest that the A2B receptor mediates these responses in HMC-1 human mast cells. Another published report also suggests that activation of A2B receptors is responsible for triggering interleukin-8 release from human HMC-1 mast cells (Feoktistov I, Biaggioni I: Adenosine A.sub.2B receptors evoke interleukin-8 secretion in human mast cells--An enprofylline-sensitive mechanism with implications for asthma. J. Clin. Invest. 1995;96: 1979-1986).
8-Phenylxanthines, methods of their synthesis and their use in human and veterinary therapy for conditions associated with the cell surface effects of adenosine have been described (EP 0 203 721, published Dec. 13, 1986). However, this publication is silent as to whether adenosine receptors mediate this response and if so, which adenosine receptor subtype. Also, the subtype specificity of disclosed compounds is not described. In WO 90/00056, a group of 1,3-unsymmetrical straight chain alkyl-substituted 8-phenylxanthines were described as being potent bronchodilators. This disclosure is likewise silent as to the role of adenosine and the subtype specificity of disclosed compounds.
Methods of treating conditions related to the physiological action of adenosine have, to date, proven inferior due to the presence of multiple subtypes present in the animal tissue utilized (R. F. Bruns et al., (1986) Mol. Pharm. 29:331-346) and the differences between species in the affinity for adenosine analogs and the physiological effects of adenosine (Ukera et al., (1986) FEBS Lett, 209:122-128).